Purpose: To assess baseline factors that may predict fast tibiofemoral cartilage loss over a 30-month period. Materials and Methods: The Multicenter Osteoarthritis (MOST) study is a longitudinal study of individuals who have or who are at high risk for knee osteoarthritis. The HIPAA-compliant protocol was approved by the institutional review boards of all participating centers, and written informed consent was obtained from all participants. Magnetic resonance (MR) images were read according to the Whole-Organ Magnetic Resonance Imaging Score (WORMS) system. Only knees with minimal baseline cartilage damage (WORMS ≤ 2.5) were included. Fast cartilage loss was defined as a WORMS of at least 5 (large full-thickness loss, less than 75% of the subregion) in any subregion at 30-month follow-up. The relationships of age, sex, body mass index (BMI), ethnicity, knee alignment, and several MR features (eg, bone marrow lesions, meniscal damage and extrusion, and synovitis or effusion) to the risk of fast cartilage loss were assessed by using a multivariable logistic regression model. Results: Of 347 knees, 90 (25.9%) exhibited cartilage loss, and only 20 (5.8%) showed fast cartilage loss. Strong predictors of fast cartilage loss were high BMI (adjusted odds ratio [OR], 1.11; 95% confidence interval [CI]: 1.01, 1.23), the presence of meniscal tears (adjusted OR, 3.19; 95% CI: 1.13, 9.03), meniscal extrusion (adjusted OR, 3.62; 95% CI: 1.34, 9.82), synovitis or effusion (adjusted OR, 3.36; 95% CI: 0.91, 12.4), and any high-grade MR-depicted feature (adjusted OR, 8.99; 95% CI: 3.23, 25.1). Conclusion: In participants with minimal baseline cartilage damage, the presence of high BMI, meniscal damage, synovitis or effusion, or any severe baseline MR-depicted lesions was strongly associated with an increased risk of fast cartilage loss. Patients with these risk factors may be ideal subjects for preventative or treatment trials. © RSNA, 2009.